ABSTRACT In the current healthcare environment, reducing costs by eliminating a second test (such as a dedicated computed tomography [CT] for CAC) when clinically similar data is already available (such as from a non- contrast chest CT (NCCT) ordered for another indication) is a laudable goal. More importantly, many cardiac events could potentially be prevented if incidentally discovered CAC or aortic arch calcification (AAC) would not only alert physicians to the presence of significant disease but would steer appropriate patients for lifestyle and/or pharmacologic intervention. Finally, evaluating those with high CAC scores who do not suffer an event over the next 20 years will identify factors that are protective, and can potentially reduce false positives associated with CAC testing, avoiding downstream testing and medication use. The concomitant assessment of CAC during lung cancer screening with NCCT, represents an opportunity to also identify asymptomatic individuals at both decreased and increased cardiovascular (CVD) risk. Furthermore, evaluating advanced metrics of CAC (ie- density and location) along with AAC to improve CAC performance, is unique. This study poses to leverage the Multi-Ethnic Study of Atherosclerosis (MESA) as a rigorously compiled and highly validated dataset using a comprehensively phenotyped, multi-racial and multi-ethnic cohort. We will utilize the considerable resources already invested in the collection of almost 20,000 well performed NCCT to determine prevalence, risk factor associations, and prognostic value using 20 years of careful adjudicated CVD follow up and repeat imaging. Specifically, we will measure AAC, CAC, and density in 19,861 scans: 6,814 participants in the baseline study and 5,987 full lung CTs in participants of MESA Lung Study (3,187 in 2010- 12) and 2850 acquired during exam 6 (2016-2018). The scientific premise is that these extra-coronary calcifications (ECC) may portend risk for CVD independent of CAC, and that non-contrast CT (such as those obtained for lung cancer screening) can serve as a viable source of both CAC and ECC measurement. The MESA Cohort permits a unique opportunity, with over 20 year follow up and committee adjudicated CVD events, to allow establishment of prevalence and prognostic significance of CAC detection in a multi-ethnic population based cohort, with consideration of prognostic potential of both calcium density and AAC. The hope is that this may serve as a mechanism to deliver appropriate preventative treatment, emphasizing therapeutic intervention for those who are at higher predicted risk at a given CAC threshold. These aspects are highly innovative, as is the emphasis on evaluating calcium density as a de-risking, effect modifier for individuals with higher CAC is unique to our knowledge. With achievement of the proposed study aims, a valuable epidemiological database will be developed, and the opportunity to utilize existing NCCT for routine CVD risk stratification will move closer to reality. We feel the proposal is highly significant with considerable potential to exert a direct, positive impact on the approach to CVD prevention.